Highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using same

ABSTRACT

The present invention relates to highly enantiomerically pure lactam-substituted propanoic acid derivatives and methods of making and using therefor. The invention involves a multi-step synthesis to produce the lactam compounds. In one step of the reaction sequence, asymmetric hydrogenation of a lactam-enamide was performed to produce an intermediate that can ultimately be converted to a series of pharmaceutical compounds. The invention also contemplates the in situ synthesis of an intermediate of the multi-step synthesis, which provides economic advantages to the overall synthesis of the lactam compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of Non-provisionalapplication Ser. No. 09/957,182, filed Sep. 20, 2001, and now issued asU.S. Pat. No. 6,686,477, which claims priority to U.S. ProvisionalApplication No. 60/236,564, filed Sep. 29, 2000, and U.S. ProvisionalApplication No. 60/264,411, filed Jan. 26, 2001, both entitled“Phosphino-Aminophosphines,” which applications are hereby incorporatedby this reference in their entireties.

BACKGROUND OF THE INVENTION

Asymmetric catalysis is the most efficient method for the generation ofproducts with high enantiomeric purity, as the asymmetry of the catalystis multiplied many times over in the generation of the chiral product.These chiral products have found numerous applications as buildingblocks for single enantiomer pharmaceuticals as well as in someagrochemicals. The asymmetric catalysts employed can be enzymatic orsynthetic in nature. The latter types of catalyst have much greaterpromise than the former due to much greater latitude of applicablereaction types. Synthetic asymmetric catalysts are usually composed of ametal reaction center surrounded by an organic ligand. The ligandusually is generated in high enantiomeric purity, and is the agentinducing the asymmetry. A prototypical reaction using these types ofcatalyst is the asymmetric hydrogenation of enamides to affordamino-acid derivatives (Ohkuma, T.; Kitamura, M.; Noyori, R. InCatalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: NewYork, 2000; pp. 1-17).

Although the preparation of enamides through Horner-Emmons Wittigchemistry is known, the preparation and use of substrates such aslactam-substituted 2-propenoic acid derivatives which possess a fullysubstituted nitrogen on the enamide are not known and the viability ofthe standard preparative sequence for the enamide is unclear. Ingeneral, the majority of enamides that have undergone asymmetrichydrogenation possess a hydrogen substituent on the nitrogen of theenamide. Thus the efficacy of asymmetric catalysts for the hydrogenationof lactam-substituted 2-propenoic acid derivatives is also unclear.

U.S. Pat. No. 4,696,943 discloses the synthesis of single enantiomerlactam-substituted propanoic acid derivatives useful as pharmaceuticalagents for various conditions. However, these compounds were prepared bya cyclization reaction and not by the asymmetric hydrogenation of anenamide.

In light of the above, it would be desirable to produce singleenantiomer lactam-substituted propanoic acid derivatives useful aspharmaceutical compounds.

SUMMARY OF THE INVENTION

The present invention relates to highly enantiomerically purelactam-substituted propanoic acid derivatives and methods of making andusing therefor. The invention involves a multi-step synthesis to producethe lactam compounds. In one step of the reaction sequence, asymmetrichydrogenation of a lactam-enamide was performed to produce anintermediate that can ultimately be converted to a series ofpharmaceutical compounds. The invention also contemplates the in situsynthesis of an intermediate of the multi-step synthesis, which provideseconomic advantages to the overall synthesis of the lactam compounds.

Additional advantages of the invention will be set forth in part in thedescription that follows, and in part will be apparent from thedescription or may be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of aspects of the invention and theExamples included therein.

Before the present compositions of matter and methods are disclosed anddescribed, it is to be understood that this invention is not limited tospecific synthetic methods or to particular formulations, and, as such,may, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting.

The singular forms a, an, and the include plural referents unless thecontext clearly dictates otherwise.

Optional or optionally means that the subsequently described event orcircumstances may or may not occur, and that the description includedinstances where said event or circumstance occurs and instances where itdoes not.

The term “alkyl group” may include straight- or branched-chain,aliphatic hydrocarbon radicals containing up to about 20 carbon atomsand may be substituted, for example, with one to three groups selectedfrom C₁-C₆-alkoxy, cyano, C₂-C₆-alkoxycarbonyl, C₂-C₆ alkanoyloxy,hydroxy, aryl and halogen. The terms “C₁-C₆-alkoxy,”“C₂-C₆-alkoxycarbonyl,” and “C₂-C₆-alkanoyloxy” are used to denoteradicals corresponding to the structures —OR, —CO₂R, and —OCOR,respectively, wherein R is C₁-C₆-alkyl or substituted C₁-C₆-alkyl.

The term “cycloalkyl” is used to denote a saturated, carbocyclichydrocarbon. The term “substituted cycloalkyl” is a cycloalkyl groupsubstituted with one or more of the groups described above.

The term “aryl group” may include phenyl, naphthyl, or anthracenyl andphenyl, naphthyl, or anthracenyl substituted with one to threesubstituents selected from C₁-C₆-alkyl, substituted C₁-C₆-alkyl, C₆-C₁₀aryl, substituted C₆-C₁₀ aryl, C₁-C₆-alkoxy, halogen, carboxy, cyano,C₁-C₆-alkanoyloxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfonyl,trifluoromethyl, hydroxy, C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoylamino and—OR′, SR′, —SO₂R′, —NHSO₂R′ and —NHCO₂R′, wherein R′ is phenyl,naphthyl, or phenyl or naphthyl substituted with one to three groupsselected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy and halogen.

The term “heteroaryl group” includes a 5- or 6-membered aromatic ringcontaining one to three heteroatoms selected from oxygen, sulfur andnitrogen. Examples of such heteroaryl groups are thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl,pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and thelike. The heteroaryl group may be substituted, for example, with up tothree groups such as C₁-C₆-alkyl, C₁-C₆-alkoxy, substituted C₁-C₆-alkyl,halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy, C₂-C₆-alkoxycarbonyland C₂-C₆-alkanoylamino. The heteroaryl group also may be substitutedwith a fused ring system, e.g., a benzo or naphtho residue, which may beunsubstituted or substituted, for example, with up to three of thegroups set forth in the preceding sentence.

Reference will now be made in detail to the present aspects of theinvention. Wherever possible, the same reference numbers and letters areused throughout the various formulas in the invention to refer to thesame or like parts.

The present invention relates to the synthesis of enantiomerically purelactam-substituted propanoic acid derivatives and methods of making andusing therefor. A reaction scheme that depicts a general sequence ofreaction steps to produce the compounds of the invention is shown inScheme 1.

The first step depicted in Scheme 1 involves the reaction (i.e.,condensation) between a compound having the formula I

with glyoxylic acid, wherein R¹ is hydrogen, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl; substitutedor unsubstituted C₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ toC₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀ heteroaryl, andn is from 0 to 5,to produce a compound having the formula II.

The condensation reaction between lactam I and glyoxylic acid isgenerally conducted in a solvent. Examples of useful solvents include,but are not limited to, aliphatic hydrocarbons such as hexane, heptane,octane and the like, aromatic hydrocarbons such as toluene, xylenes, andthe like, cyclic or acyclic ethers such as diethyl ether, tert-butylmethyl ether, diisopropyl ether, tetrahydrofuran and the like, or polaraprotic solvents such as dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone and the like. The amount of glyoxylic acid relativeto the amount of compound I can vary. In one aspect, the glyoxylic acidis present in the amount from 0.8 to 2 equivalents per 1.0 equivalent ofthe compound having the formula I. The condensation reaction isgenerally run between ambient temperature and the boiling point of thelowest boiling component of the mixture.

The second step depicted in Scheme 1 involves converting compound II toa compound having the formula III

wherein R¹, R³, and R⁴ are, independently, a substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl group; asubstituted or unsubstituted C₃ to C₈ cycloalkyl group; a substituted orunsubstituted C₆ to C₂₀ aryl group; or a substituted or unsubstituted C₄to C₂₀ heteroaryl group, wherein R¹ can also be hydrogen, and n is from0 to 5.

The second step generally involves reacting a compound having theformula II with an alcohol comprising an alkyl alcohol, an aryl alcohol,or a heteroaryl alcohol, wherein the alkyl alcohol is substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl or substitutedor unsubstituted C₃ to C₈ cycloalkyl; the aryl alcohol is substituted orunsubstituted C₆ to C₂₀ aryl; and the heteroaryl alcohol is substitutedor unsubstituted C₄ to C₂₀ heteroaryl, wherein the heteroatom is oxygen,nitrogen, or sulfur. Although R³ and R⁴ need not be the same group, theycan be derived from the same alcohol. In one aspect, the alcohol is a C₁to C₅ alcohol, preferably methanol or ethanol. The amount of alcoholthat is used can vary. In one aspect, the alcohol is present in theamount from 2.0 to 5.0 equivalents per 1.0 equivalent of the compoundhaving the formula II.

In another aspect, the second step is generally conducted underdehydrating conditions using acid catalysis. For example, the use of adehydrating agent such as a trialkyl orthoformate or the physicalremoval of water from the reaction mixture via an azeotropicdistillation are useful in the present invention. When a dehydratingagent is used, the amount of dehydrating agent used relative to theamount of compound II is generally between 2 and 5 molar equivalents. Ingeneral, the alcohol can be used as the reaction solvent for thepreparation of compound III; however, co-solvents can be used. Examplesof co-solvents useful in the present invention include, but are notlimited to, aliphatic hydrocarbons such as hexane, heptane, octane andthe like, aromatic hydrocarbons such as toluene, xylenes, and the like.A preferable co-solvent is toluene or xylene. The second step isgenerally performed at a temperature between ambient temperature and theboiling point of the lowest boiling component of the reaction mixture.In one aspect, the reaction is performed between 20° C. and 120° C.

The compounds produced in steps 1 and 2 can be represented by thegeneral formula XI

wherein R¹, R³, and R⁴ are, independently, hydrogen, a substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl group; asubstituted or unsubstituted C₃ to C₈ cycloalkyl group; a substituted orunsubstituted C₆ to C₂₀ aryl group; or substituted or unsubstituted C₄to C₂₀ heteroaryl group, and n is from 0 to 5. In one aspect, n is 2. Inanother aspect, R¹, R³, and R⁴ are hydrogen and n is 2. In a furtheraspect, R¹ is hydrogen, R³ and R⁴ are methyl, and n is 2.

The third step in Scheme 1 involves converting compound III to thehalogenated lactam compound having the formula IV

wherein R¹ and R³ are, independently, substituted or unsubstituted,branched or straight chain C₁ to C₂₀ alkyl; substituted or unsubstitutedC₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ to C₂₀ aryl; orsubstituted or unsubstituted C₄ to C₂₀ heteroaryl, wherein R¹ can alsobe hydrogen, X is fluoride, chloride, bromide, or iodide, and n is from0 to 5.

The third step generally involves reacting compound III with aphosphorous trihalide having the formula PX₃, wherein X is fluoro,chloro, bromo, or iodo. In one aspect of the invention, the phosphoroustrihalide is phosphorous trichloride or phosphorous tribromide. Theamount of the phosphorus trihalide is generally between 0.8 and 2.0molar equivalents based on compound III. Typically, the reaction isperformed in an inert solvent including, but not limited to, aliphatichydrocarbons such as hexane, heptane, octane and the like, aromatichydrocarbons such as toluene, xylenes, and the like, and halogenatedhydrocarbons such as dichloromethane, dichloroethane,tetrachloroethylene, chlorobenzene, and the like. The third step isgenerally performed at a temperature between ambient temperature and theboiling point of the lowest boiling component of the reaction mixturefor a time necessary to consume the majority of compound III. In oneaspect, the reaction solvent is toluene or xylene and the reactiontemperature is between 40° C. and 80° C.

The fourth step in Scheme 1 involves converting compound IV to acompound having the formula V

wherein R¹ and R³ are, independently, substituted or unsubstituted,branched or straight chain C₁ to C₂₀ alkyl; substituted or unsubstitutedC₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ to C₂₀ aryl; orsubstituted or unsubstituted C₄ to C₂₀ heteroaryl, wherein R¹ can alsobe hydrogen,R⁶ is substituted or unsubstituted, branched or straight chain C₁ to C₂₀alkyl or substituted or unsubstituted C₃ to C₈ cycloalkyl, andn is from 0 to 5. In one aspect, n is 2 and R¹ is hydrogen. In anotheraspect of the invention, R³ is methyl or ethyl. In a further aspect, R⁶is methyl or ethyl.

The fourth step is an Arbuzov reaction comprising reacting a compoundhaving the formula IV with a phosphite having the formula P(OR⁶)₃,wherein R⁶ is substituted or unsubstituted, branched or straight chainC₁ to C₂₀ alkyl or substituted or unsubstituted C₃ to C₈ cycloalkyl. Inone aspect, the phosphite is trimethyl phosphite or triethyl phosphite.In another aspect of the invention, compound IV is the chloro or bromocompound (X=Cl or Br). The amount of the phosphite is generally between0.8 and 1.2 molar equivalents based on compound IV. The reaction isoptionally conducted in the presence of a solvent including, but notlimited to, aliphatic hydrocarbons such as hexane, heptane, octane andthe like, aromatic hydrocarbons such as toluene, xylenes, and the like,cyclic or acyclic ethers such as tert-butyl methyl ether, diisopropylether, tetrahydrofuran and the like, halogenated hydrocarbons such asdichloromethane, dichloroethane, tetrachloroethylene, chlorobenzene andthe like, or polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like. The reaction is generallyperformed at a temperature between ambient temperature and the boilingpoint of the lowest boiling component of the reaction mixture for a timenecessary to consume the majority of compound IV. In one aspect, thesolvent is toluene or xylene and the reaction is performed between 40°C. and 100° C.

The fifth step in Scheme 1 involves converting compound V to a compoundhaving the formula VI

wherein R¹, R², and R³ are, independently, hydrogen, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl; substitutedor unsubstituted C₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ toC₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀ heteroaryl, and n isfrom 0 to 5. In one aspect, n is 2 and R¹ is hydrogen. In anotheraspect, R² and R³ are methyl. In a further aspect, R² is methyl and R³is ethyl.

The fifth step of the sequence is a Horner-Emmons Wittig reactionbetween phosphonate compound V and an aldehyde having the formulaHC(O)R² to afford enamide VI. In one aspect of the invention, thealdehyde is acetaldehyde. The reaction generally involves the use of abase. For example, the base can be a moderately strong non-hydroxidebase with a pKa of about 13 or above. Examples of non-hydroxide basesinclude, but are not limited to, amidine bases such as1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or guanidine bases such astetramethylguanidine (TMG). The amount of base is usually between 1.0and 2.0 molar equivalents based on compound V, and the amount ofaldehyde is generally between 0.8 and 1.5 molar equivalents basedcompound V.

The reaction to produce compound VI is generally conducted in thepresence of a solvent. Solvents useful in the reaction include, but arenot limited to, aliphatic hydrocarbons such as hexane, heptane, octaneand the like, aromatic hydrocarbons such as toluene, xylenes, and thelike, cyclic or acyclic ethers such as tert-butyl methyl ether,diisopropyl ether, tetrahydrofuran and the like, halogenatedhydrocarbons such as dichloromethane, dichloroethane,tetrachloroethylene, chlorobenzene and the like, or polar aproticsolvents such as dimethylformamide, dimethyl sulfoxide,N-methylpyrrolidone and the like. The reaction is generally performed ata temperature between −80° C. and the boiling point of the lowestboiling component of the reaction mixture for a time necessary tolargely consume compound V. In one aspect of the invention, the reactionis performed in toluene or xylene at a temperature of 0° C. to 50° C.

The invention also contemplates producing compound VI from compound IIIin situ. The term “in situ” is defined herein as performing two or morereaction sequences without isolating any of the intermediates that areproduced during the reaction sequence. One aspect of the inventioninvolves a method for producing the compound VI in situ, comprising

-   (a) reacting a compound having the formula III    -   wherein R³ and R⁴ are a substituted or unsubstituted, branched        or straight chain C₁ to C₂₀ alkyl group; a substituted or        unsubstituted C₃ to C₈ cycloalkyl group; a substituted or        unsubstituted C₆ to C₂₀ aryl group; or substituted or        unsubstituted C₄ to C₂₀ heteroaryl group, wherein R¹ can also be        hydrogen,    -   with PX₃, wherein X is fluoride, chloride, bromide, or iodide,        to produce a halogenated lactam;-   (b) reacting the halogenated lactam produced in step (a) with a    phosphite having the formula P(OR⁶)₃, wherein R⁶ is substituted or    unsubstituted, branched or straight chain C₁ to C₂₀ alkyl or    substituted or unsubstituted C₃ to C₈ cycloalkyl, to produce a    phosphonated lactam; and-   (c) reacting the phosphonated lactam produced in step (b) with an    aldehyde having the formula HC(O)R², wherein R² is hydrogen,    substituted or unsubstituted, branched or straight chain C₁ to C₂₀    alkyl; substituted or unsubstituted C₃ to C₈ cycloalkyl; substituted    or unsubstituted C₆ to C₂₀ aryl; or substituted or unsubstituted C₄    to C₂₀ heteroaryl,    -   in the presence of a base,        wherein steps (a), (b), and (c) are performed in situ. In this        aspect of the invention, compounds IV and V are not isolated.        The in situ preparation of compound VI would not have been        expected due to the incompatibility of several of the reagents        used in the in situ process. In addition, there is an economic        advantage to combining multiple reaction steps without having to        isolate each of compound that is produced.

The sixth step in Scheme 1 involves converting compound VI to a compoundhaving the formula VII

wherein R¹, R², and R³ are, independently, hydrogen, a substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl group; asubstituted or unsubstituted C₃ to C₈ cycloalkyl group; a substituted orunsubstituted C₆ to C₂₀ aryl group; or substituted or unsubstituted C₄to C₂₀ heteroaryl group,n is from 0 to 5, andthe stereochemistry at carbon a is substantially R or S.

The term “substantially R or S” refers to the enantiomeric purity of theaformentioned compound, which is measured by the enantiomeric excess ofthis material. The enantiomeric excess (ee) is defined as the percent ofone enantiomer of the mixture minus the percent of the other enantiomer.“Substantially R” indicates an ee of 90% or greater with the Renantiomer the major enantiomer, whilst “substantially S” indicates anee of 90% or greater with the S enantiomer the major enantiomer. In oneaspect of the invention, the stereochemistry at carbon a issubstantially S. In another aspect of the invention, the stereochemistryat carbon a is substantially R.

In other aspects of the invention, the heteroatom of the heteroarylgroup in compound VII is oxygen, sulfur, or nitrogen, and thesubstituent on the substituted alkyl, aryl, or heteroaryl groupcomprises alkyl, aryl, hydroxy, alkoxy, fluoro, chloro, bromo, iodo,nitro, cyano, or an ester; R² and R³ are independently selected frommethyl or ethyl; R¹ is hydrogen, R² is methyl, R₃ is methyl or ethyl;and n is 2.

The conversion of compound VI to compound VII comprises hydrogenatingcompound VI with hydrogen in the presence of a catalyst comprised of achiral ligand/metal complex to asymmetrically hydrogenate thecarbon-carbon double bond of compound VI. The term “hydrogenate”generally refers to reacting a carbon-carbon double or triple bond withhydrogen to reduce the degree of unsaturation. For example, thecarbon-carbon double bond of compound VI is hydrogenated to produce acarbon-carbon single bond. Here, the degree of unstauration has beenreduced by one. Referring to Scheme 2, hydrogen can be added to side b(front side) or c (back side) of the carbon-carbon double bond ofcompound VII. The stereochemistry at carbon a of compound VII will bedetermined by which side of the carbon-carbon double bond hydrogenapproaches. The term “asymmetrically hydrogenating” refers to theaddition of hydrogen to a particular side or face (b or c) of thecarbon-carbon double bond of compound VII in preference to the otherside. The degree of asymmetric hydrogenation is described by theenantiomeric excess of the asymmetric hydrogenation product.

The asymmetric hydrogenation of compound VI involves the use of a chiralligand/metal complex. The chiral ligand/metal complex is composed of achiral ligand and a metal, where the metal is either chemically bondedto the chiral ligand or the metal is coordinated to the chiral ligand.Any chiral ligand/metal complex known in the art can be used toasymmetrically hydrogenate compound VI. For example, the chiralligand/metal complexes disclosed in Ohkuma et al. in CatalyticAsymmetric Synthesis, 2nd Ed, Wiley-VCH, 2000, pages 1-17, which isincorporated by reference in its entirety, are useful in the presentinvention.

In one aspect of the invention, the chiral ligand of the chiralligand/metal complex comprises the substantially pure enantiomer ordiastereomer of2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane;2,2′-bis(diphenylphosphino)-1,1′-binaphthyl;1,2-bis-2,5-dialkylphospholano(benzene);1,2-bis-2,5-dialkylphospholano(ethane);2,3-bis-(diphenylphosphino)butane; or2-diphenylphosphinomethyl-4-diphenylphophino-1-t-butoxycarbonylpyrrolidine.

In another aspect of the invention, the chiral ligand of the chiralligand/metal complex comprises a substantially enantiomerically purebis-phosphine compound comprising one phosphine residue having threephosphorus-carbon bonds and the other having two phosphorus-carbon bondsand one phosphorus-nitrogen bond. In one aspect of the invention, thechiral ligand of the chiral ligand/metal complex comprises a phosphineor a bis-phosphine compound and the metal of the chiral ligand/metalcomplex comprises rhodium, ruthenium, or iridium.

Examples of substantially enantiomerically pure bis-phosphine compounds,e.g., an enantiomeric excess of 90% or greater, includephosphinometallocenyl-aminophosphines having the general formulas IX andX (the enantiomer of IX):

where R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are, independently, hydrogen,substituted or unsubstituted branched or straight chain C₁ to C₂₀ alkyl,substituted or unsubstituted C₃ to C₈ cycloalkyl, substituted orunsubstituted C₆ to C₂₀ aryl, and substituted or unsubstituted C₄ to C₂₀heteroaryl, where the heteroatoms are chosen from sulfur, nitrogen, oroxygen, provided R¹² is not hydrogen;a is from 0 and 3;b is from 0 and 5; andM is a Group IV to Group VIII metal. The synthesis of the chiral ligandshaving the formulas IX and X is disclosed in U.S. ProvisionalApplication Nos. 60/236,564 and 60/264,411, both of which areincorporated by reference in their entireties.

The alkyl groups that may be represented by each of R⁷, R⁸, R⁹, R¹⁰,R¹¹, and R¹² in formulas IX and X may be straight- or branched-chain,aliphatic hydrocarbon radicals containing up to about 20 carbon atomsand may be substituted, for example, with one to three groups selectedfrom C₁-C₆-alkoxy, cyano, C₂-C₆-alkoxycarbonyl, C₂-C₆ alkanoyloxy,hydroxy, aryl and halogen. The terms “C₁-C₆-alkoxy,”“C₂-C₆-alkoxycarbonyl,” and “C₂-C₆-alkanoyloxy” are used to denoteradicals corresponding to the structures —OR¹³, —CO₂R¹³, and —OCOR¹³,respectively, wherein R¹³ is C₁-C₆-alkyl or substituted C₁-C₆-alkyl. Theterm “C₃-C₈-cycloalkyl” is used to denote a saturated, carbocyclichydrocarbon radical having three to eight carbon atoms.

The aryl groups for each of R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² in formulas IXand X may include phenyl, naphthyl, or anthracenyl and phenyl, naphthyl,or anthracenyl substituted with one to three substituents selected fromC₁-C₆-alkyl, substituted C₁-C₆-alkyl, C₆-C₁₀ aryl, substituted C₆-C₁₀aryl, C₁-C₆-alkoxy, halogen, carboxy, cyano, C₁-C₆-alkanoyloxy,C₁-C₆-alkylthio, C₁-C₆-alkylsulfonyl, trifluoromethyl, hydroxy,C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoylamino and —O—R¹⁴, S—R¹⁴, —SO₂—R¹⁴,—NHSO₂R¹⁴ and —NHCO₂R¹⁴, wherein R¹⁴ is phenyl, naphthyl, or phenyl ornaphthyl substituted with one to three groups selected from C₁-C₆-alkyl,C₆-C₁₀ aryl, C₁-C₆-alkoxy and halogen.

The heteroaryl radicals include a 5- or 6-membered aromatic ringcontaining one to three heteroatoms selected from oxygen, sulfur andnitrogen. Examples of such heteroaryl groups are thienyl, furyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl,pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl and thelike. The heteroaryl radicals may be substituted, for example, with upto three groups such as C₁-C₆-alkyl, C₁-C₆-alkoxy, substitutedC₁-C₆-alkyl, halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy,C₂-C₆-alkoxycarbonyl and C₂-C₆-alkanoylamino. The heteroaryl radicalsalso may be substituted with a fused ring system, e.g., a benzo ornaphtho residue, which may be unsubstituted or substituted, for example,with up to three of the groups set forth in the preceding sentence. Theterm “halogen” is used to include fluorine, chlorine, bromine, andiodine.

In one aspect of the invention, when the chiral ligand is a compoundhaving the formula IX or X, R¹² is C₁ to C₆ alkyl (e.g., methyl); R⁷ ishydrogen or C₁ to C₆ alkyl (e.g., methyl); R⁸ is aryl (e.g., phenyl),ethyl, isopropyl, or cyclohexyl; R⁹ is aryl (e.g., phenyl); R¹⁰ and R¹¹are hydrogen; and M is iron, ruthenium, or osmium.

The chiral ligand/metal complex can be prepared and isolated, or, in thealternative, it can be prepared in situ. The preparation of chiralligand/metal complexes is generally known in the art. The chiral ligandto metal molar ratio can be from 0.5:1 to 5:1, preferably from 1:1 to1.5:1. The amount of chiral ligand/metal complex may vary between 0.0005and 0.5 equivalents based on compound VI, with more catalyst leading toa faster reaction.

The hydrogenation reaction is conducted under an atmosphere of hydrogen,but other materials that are inert to the reaction conditions may alsobe present. The reaction can be run at atmospheric pressure or atelevated pressure of from 0.5 to 200 atmospheres. The reactiontemperature can be varied to modify the rate of conversion, usuallybetween ambient temperature and the boiling point (or apparent boilingpoint at elevated pressure) of the lowest boiling component of thereaction mixture. In one aspect of the invention, the hydrogenation stepis conducted at from −20° C. to 100° C. The reaction is usually run inthe presence of a solvent. Examples of useful solvents include, but arenot limited to, aliphatic hydrocarbons such as hexane, heptane, octaneand the like, aromatic hydrocarbons such as toluene, xylenes, and thelike, cyclic or acyclic ethers such as tert-butyl methyl ether,diisopropyl ether, tetrahydrofuran and the like, dialkyl ketones such asacetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone andthe like, or polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like.

Compounds having the formula VII can be converted to the amide compoundsVIII

wherein R¹ and R² are, independently, hydrogen, substituted orunsubstituted, branched or straight chain C₁ to C₂₀ alkyl; substitutedor unsubstituted C₃ to C₈ cycloalkyl; substituted or unsubstituted C₆ toC₂₀ aryl; or substituted or unsubstituted C₄ to C₂₀ heteroaryl,n is from 0 to 5, andthe stereochemistry at carbon a is substantially R or S,comprising reacting a compound having the formula VII with NH₄OH.

The amount of NH₄OH can vary, wherein from 1 to 10 equivalents of NH₄OHper 1.0 equivalent of the compound having the formula VII can be used.The reaction is generally performed in water optionally in the presenceof a water-miscible organic solvent, including, but not limited to, alower alcohol such as methanol or ethanol, THF, DMF, or DMSO. Thereaction is preferably performed in water as the sole solvent. Thereaction temperature can also vary, however; the reaction is typicallyperformed from 0° C. to 50° C. The compounds having the formula VIII canbe used to treat a number of different maladies, some of which aredisclosed in U.S. Pat. No. 4,696,943, which is incorporated by referencein its entirety.

In summary, the invention provides lactam-substituted propanoic acidderivatives that are useful precursors to enantiomerically-purelactam-substituted propanoic acid derivatives. The invention provides anefficient method for making the lactam-substituted propanoic acidderivatives as well as the enantiomerically enriched compounds, whichwill ultimately be used to produce pharmaceutical compounds.

Throughout this application, where publications are referenced, thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompositions of matter and methods claimed herein are made andevaluated, and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.) but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are by weight, temperature is in ° C. or is at roomtemperature and pressure is at or near atmospheric.

Example 1 Preparation of Methyl 2-(2-Pyrrolidino)propanoate

Step 1: Preparation of Hydroxy-acid 2a (Formula II, n=2, R¹=R³=R⁴=H):

Glyoxylic acid monohydrate (20.2 g; 220 mmol; 1.1 equiv) was slurried in200 mL of diethyl ether. Pyrrolidinone (15.2 mL; 200 mmol) was added andthe resulting mixture was stirred at ambient temperature for two days toafford a white precipitate. The precipitate was isolated by filtration,washed with ether, and air-dried to afford 36.06 g (99%) of hydroxy-acid2a.

¹H NMR (DMSO-d₆) δ 5.55 (s, 1H); 3.5-3.3 (m, 2H); 3.36 (s, 3H); 2.46 (m,2H); 2.07 (m, 2H).

Step 2: Preparation of Ether-ester 3a (Formula III, n=2, R¹=H,R³=R⁴=Me):

Hydroxy-acid 2a (25.3 g; 160 mmol) was dissolved in methanol (370 mL),cooled in ice-water, and treated with concentrated sulfuric acid (5.0mL; 0.093 mmol; 0.57 molar equiv). The reaction mixture was allowed towarm to ambient temperature and allowed to stir for 5 days. Solid sodiumbicarbonate (17.1 g; 203 mmol; 1.27 equiv) was added and the reactionmixture was stirred for 30 min. The reaction mixture was filtered andthe filtrate was concentrated. The resulting material was diluted withwater (25 mL) and extracted with ethyl acetate (2×50 mL). The combinedextracts were dried with magnesium sulfate and the solvent wasevaporated to afford 22.84 g (76%) of 3a.

¹H NMR (CDCl₃) δ 5.64 (s, 1H); 3.78 (s, 3H); 3.40 (m, 1H); 3.16 (m, 1H);2.24 (m, 2H); 1.90 (m, 2H).

Steps 3 and 4: Preparation of Phosphonate Ester 5a (formula V n=2, R¹=H,R³=R⁶=Me):

Ether-ester 3a (9.36 g; 50 mmol) was dissolved in 50 mL of toluene. Thereaction mixture was heated to 70° C. and phosphorus trichloride (4.36mL; 50 mmol; 1.0 equiv) was added. The reaction mixture was heated at70° C. for 18 h to afford chloride 4a (formula IV, X=Cl, R³=Me).Trimethyl phosphite (5.9 mL; 50 mmol; 1.0 equiv) was then added. Theresulting mixture was heated for 36 h and then cooled to ambienttemperature. The volatiles were stripped at reduced pressure and theremaining material was dissolved in 100 mL of ethyl acetate. The mixturewas washed with saturated aqueous sodium bicarbonate (2×25 mL), and theresulting aqueous solution was back-extracted three times with ethylacetate. The combined ethyl acetate solution was dried with magnesiumsulfate and concentrated to afford 4.35 g (33%) of phosphonate 5a.

¹H NMR (CDCl₃) δ 5.46 (d, 1H, J_(P-H)=24.72 Hz); 3.84 (d, 3H,J_(P-H)=10.99 Hz); 3.80 (s, 3H); 3.78 (d, 3H, J_(P-H)=11.26 Hz) 3.8 (m,1H); 3.66 (m, 1H); 2.42 (m, 2H); 2.08 (m, 2H).

Step 5: Preparation of Enamide 6a (Formula VI, n=2, R=H, R²=R³=Me):

Phosphonate 5a (2.65 g; 10 mmol) was dissolved in 10 mL oftetrahydrofuran. The mixture was cooled to −78° C. andtetramethylguanidine (2.88 mL; 15 mmol; 1.5 equiv) was added. Thereaction mixture was stirred for 15 min and acetaldehyde (0.84 mL; 15mmol; 1.5 equiv) was added. The resulting mixture was stirred at −78° C.for 1 h and then warmed to ambient temperature and stirred overnight.The volatiles were evaporated at reduced pressure and water (10 mL) wasadded. The mixture was extracted three times with ethyl acetate and thecombined extracts were dried with magnesium sulfate and concentrated.The crude product was filtered through a pad of flash silica gel andeluted with ethyl acetate to afford 1.37 g (75%) of 6a as a mixture of Eand Z isomers.

E-6a: ¹H NMR (CDCl₃) δ 7.05 (q, 1H, J=7.14 Hz); 3.74 (s, 3H); 3.55 (t,2H, J=6.86 Hz); 2.46 (m, 2H); 2.15 (m, 2H); 1.77 (d, 3H, J=7.19 Hz).

Z-6a: ¹H NMR (CDCl₃) δ 5.99 (q, 1H, J=7.42 Hz); 3.78 (s, 3H); 2.02 (d,3H, J=7.42 Hz).

Step 6: Hydrogenation of Enamide 6a to Afford Ester 7a (Formula VII,n=2, R¹=H, R²=R³=Me) using Ligand 9a (Formula IX, R¹²=R⁷=Me, R⁸=R⁹=Ph,a=b=0, M=Fe):

A Fischer-Porter tube was charged with ligand 9a (22 mg, 0.036 mmol;0.064 equiv) and anhydrous THF (4.0 mL) under an argon atmosphere. Argonwas bubbled through the solution for 20 minutes before the addition ofbis(1,5-cyclooctadienyl)rhodium trifluoromethanesulfonate (12 mg; 0.026mmol; 0.047 equiv). The solution was stirred at 25° C. for 5 minutes oruntil all bis(1,5-cyclooctadienyl)rhodium trifluoromethanesulfonate haddissolved. Enamide 5a (100 mg, 0.55 mmol) was added via syringe. Thevessel was capped and pressurized to 40 psi H₂. After 18 hours, themixture was diluted with hexane (4.0 mL) and filtered through silica gelto remove the catalyst. The product 7a was isolated as an oil (99%yield, 96.2% ee as determined by chiral GC).

¹H NMR (CDCl₃ δ 4.71-4.65 (m, 1H), 3.71 (s, 3H), 3.55-3.47 (m, 1H),3.38-3.30 (m, 1H), 2.45-2.40 (t, J=8.4 Hz, 2H), 2.12-1.97 (m, 3H),1.74-1.64 (m, 1H), 0.94-0.89 (t, J=7.5 Hz, 3H). Chiral GC analysis[Cyclosil-B (J&W Scientific), 40° C. for 4 min to 175° C. at 70° C./min,hold at 175° C. for 12 minutes: t_(R)=23.19 (major enantiomer),t_(R)=23.24 (minor enantiomer)].

Example 2

In Situ Preparation of Compound VI (n=2, R¹=H, R²=R³=Me):

Ether-ester 3a (9.36 g; 50 mmol) was dissolved in 25 mL of toluene. Thereaction mixture was heated to 50° C. and phosphorus trichloride (4.4mL; 50 mmol; 1.0 equiv) was added and the mixture was held at 50° C. for16 h. The reaction mixture was cooled to ambient temperature and sodiumbicarbonate (10.5 g; 125 mmol; 2.5 equiv) was added. The mixture wasstirred for 15 min, filtered, and the volatiles were stripped. Thesolution was reconstituted by the addition of toluene (25 mL) and heatedto 70° C. Trimethyl phosphite (6.5 mL; 55 mmol; 1.1 equiv) was added andthe reaction mixture was heated at 70° C. for 24 h to completely consume4a. The mixture was then cooled to 2° C. and acetaldehyde (4.2 mL; 75mmol; 1.5 equiv) was added. Tetramethylguanidine (9.41 mL; 75 mmol; 1.5equiv) was then added slowly dropwise with an attendant exotherm to 8.5°C. The reaction mixture was allowed to warm to ambient temperature andstirred overnight to consume phosphonate 5a. Water (15 mL) was added andthe layers were separated. The aqueous layer was extracted with ethylacetate (2×15 mL) and the organic solutions were dried and concentratedto afford a total of 9.23 g of crude 6a. This material was filteredthrough a pad of flash silica gel and eluted with ethyl acetate toafford 7.13 g (78% overall from 3a) of 6a.

Example 3 Preparation of Ethyl 2-(2-Pyrrolidino)propanoate

Step 2: Preparation of Ether-ester 3b (Formula III, n=2, R¹=H,R³=R⁴=Et):

Hydroxy-acid 2a (7.96 g; 50 mmol) was dissolved in ethanol (25 mL), andtriethyl orthoformate (18.3 mL; 110 mmol; 2.2 equiv) was added.p-Toluenesulfonic acid (0.48 g; 2.5 mmol; 0.05 equiv) was added and thereaction mixture was heated to 60° C. for 24 h. Solid sodium bicarbonate(0.50 g; 6 mmol; 0.12 equiv) was added and the reaction mixture wasstirred for 15 min. The volatiles were evaporated at reduced pressureand the remaining material was dissolved in 1:1 toluene:ethyl acetate(25 mL), filtered, and concentrated to afford 10.25 g (95%) of 3b.

¹H NMR (CDCl₃) δ 5.72 (s, 1H); 4.24 (q, 2H, J=7.14 Hz); 3.57 (q, 2H,J=6.87 Hz); 3.5-3.3 (m, 2H); 2.47 (t, 2H, J=7.42 Hz); 2.06 (m(5), 2H,J=7.42 Hz); 1.29 (t, 3H, J=7.14 Hz); 1.25 (t, 3H, J=6.87 Hz).

Steps 3 and 4: Preparation of Phosphonate Ester 5b (Formula V, n=2,R¹=H, R³=Et, R⁶=Me):

Ether-ester 3b (5.38 g; 25 mmol) was dissolved in 12.5 mL of toluene.The reaction mixture was heated to 50° C. and phosphorus trichloride(2.2 mL; 25 mmol; 1.0 equiv) was added. The reaction mixture was heatedat 50° C. for 12 h and then at 70° C. for 24 h to completely consume 3band afford chloride 4b (formula IV, X=Cl, R³=Et). Solid sodiumbicarbonate (5.25 g; 62.5 mmol; 2.5 equiv) was added and the mixture wasstirred for 15 min. The reaction mixture was then filtered andconcentrated at reduced pressure. Toluene (12.5 mL) was added and thereaction mixture was heated to 70° C. where trimethyl phosphite (3.24mL; 25 mmol; 1.0 equiv) was added. The resulting mixture was heated at70° C. for 24 h and then cooled to ambient temperature. The volatileswere evaporated at reduced pressure to afford 7.00 g (99%) ofphosphonate 5b, which was used without further purification.

¹H NMR (CDCl₃) δ 5.43 (d, 1H, J_(P-H)=24.72 Hz); 4.25 (q, 2H, J=7.14Hz); 3.84 (d, 3H, J_(P-H)=10.99 Hz); 3.77 (d, 3H, J_(P-H)=10.99 Hz) 3.8(m, 1H); 3.66 (m, 1H); 2.40 (m, 2H); 2.06 (m, 2H); 1.29 (t, 3H, J=7.14Hz).

Step 5: Preparation of Enamide 6b (Formula VI, n=2, R¹=H, R³=Et, R²=Me):

Phosphonate 5b (7.00 g; 25 mmol) was dissolved in 12.5 mL of toluene.The mixture was cooled to 2° C. and acetaldehyde (2.1 mL; 37.5 mmol; 1.5equiv) was added. Tetramethylguanidine (3.5 mL; 27.5 mmol; 1.1 equiv)was added dropwise accompanied by a moderate exotherm. The reactionmixture was allowed to warm to ambient temperature and stirred overnightand then heated to 50° C. for 12 h to completely consume 5b. Thereaction mixture was diluted with 3 N HCl (10 mL) and the layers wereseparated. The aqueous layer was extracted twice with ethyl acetate andthe combined organic solution was dried with magnesium sulfate andconcentrated. The crude product was filtered through a pad of flashsilica gel and eluted with ethyl acetate to afford 2.85 g (58%) of 6b asa mixture of E and Z isomers.

E-6b: ¹H NMR (CDCl₃) δ 7.05 (q, 1H, J=7.14 Hz); 4.20 (q, 2H, J=7.14 Hz);3.55 (t, 2H, J=7.14 Hz); 2.48 (t, 2H, J=7.69 Hz); 2.15 (m(5), 2H, J=7.69Hz); 1.77 (d, 3H, J=7.14 Hz); 1.28 (t, 3H, J=7.14 Hz).

Z-6b: ¹H NMR (CDCl₃) δ 6.0 (q, 1H); 3.78 (s, 3H); 4.12 (q, 2H); 1.95 (d,3H).

Step 6: Hydrogenation of Enamide 6b to Afford Ester 7b (formula VII,n=1, R¹=H, R³=Et, R²=Me) Using Ligand 10a (Formula X, R¹²=R⁷=Me,R⁸=R⁹=Ph, a=b=0, M=Fe):

Bis(1,5-cyclooctadienyl)rhodium trifluoromethanesulfonate (5 μmol, 2.3mg) was placed into a reaction vessel and purged with argon for 20 min.A solution of 10a (6 μmol, 3.7 mg) in anhydrous THF (2.0 mL) wasdegassed with Ar for 20 minutes, then added via cannula to thebis(1,5-cyclooctadienyl)rhodium trifluoromethanesulfonate. This solutionwas stirred at 25° C. under Ar for 20 minutes. A solution of enamide 6b(0.5 mmol) in anhydrous THF (2.0 mL) was degassed with Ar for 20minutes, then added to the catalyst solution via cannula. The solutionwas then flushed with H₂ and pressurized to 20 psig H₂. A sample wastaken after 1 hour and analyzed for enantiomeric excess using standardchiral gas chromatography. 7b was formed in 95.0% ee with >99%conversion. Chiral GC analysis [Cyclosil-B (J&W Scientific), 30 m×0.25mm ID, film thickness 0.25 μm, 60-140° C. 40° C./min, 140° C. 30 min, 20psig He: t_(R)(minor enantiomer) 26.26 min, t_(R)(major enantiomer)26.82 min.

Example 4 Preparation of Amide

Step 1: Conversion of Ester 7a (Formula VII, n=1, R¹=H, R²=R³=Me) toAmide 8 (Formula VIII, n=1, R¹=H, R²=Me):

Ester 7a (93.6% ee; 0.93 g; 5.0 mmol) was combined with ammoniumhydroxide (28% NH₃; 1.0 mL; 15 mmol; 3 equiv) and stirred at ambienttemperature overnight, at which time tlc analysis indicated no 7a. Themixture was diluted with water (5 mL) and extracted with three 5 mLportions of dichloromethane. The combined extracts were dried withsodium sulfate and concentrated to afford 0.62 g (73%) of 8 whichpossessed 92.6% ee according to chiral GC analysis, indicating verylittle loss of enantiomeric purity. The crude product was recrystallizedfrom hot acetone (3.1 mL; 5 mL/g) by cooling to 0° C. The resultingcrystals were collected by filtration, washed with 1:1 acetone:heptane,and air-dried to afford 0.37 g (43%) of 8 which was 99.6% ee accordingto chiral GC.

¹H NMR (CDCl₃ δ 6.43 (br s, 1H); 5.72 (br s, 1H); 4.455 (dd, 1H, J=9.07,6.87 Hz); 3.38 (m, 2H); 2.40 (m, 2H); 2.1-1.9 (m, 3H); 1.67 (m, 1H);0.886 (t, 3H, J=7.42 Hz). Chiral GC analysis [Cyclosil-B (J&WScientific), 175° C. for 25 minutes, 15 psi He]: t_(R)=21.31 (Senantiomer), t_(R)=22.06 (R enantiomer)]. [α]_(D) ²²−86.7° (c 0.98,acetone).

Comparative Example Conversion of Ester 7a (Formula VII, n=1, R¹=H,R²=R³=Me) to Amide 8 (Formula VIII, n=1, R¹=H, R²=Me)

Ester 7a (93.6% ee; 0.93 g; 5.0 mmol) was dissolved in 2 mL of methanoland treated with ammonium hydroxide (28% ammonia; 1.0 mL; 15 mmol; 3equiv). The mixture was stirred at ambient temperature overnight, atwhich time tlc analysis indicated some residual 7a. Additional ammoniumhydroxide (1.0 mL; 15 mmol; 3 equiv) was added and the reaction mixturewas stirred for 2 days to completely consume 7a. The reaction mixturewas evaporated under reduced pressure and azeotroped several times withtoluene under reduced pressure to afford 0.95 g of 8 as a brown oilwhich was 89.4% ee according to chiral GC analysis, indicatingsubstantial loss of enantiomeric purity.

The invention has been described in detail with particular reference tospecific aspects thereof, but it will be understood that variations andmodifications can be effected without departing from the scope andspirit of the invention.

1. A compound having the formula V

wherein R¹ and R³ are, independently, branched or straight chain C₁ to C₂₀ alkyl; branched or straight chain C₁ to C₂₀ alkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₃ to C₈ cycloalkyl; C₃ to C₈ cycloalkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₆ to C₂₀ aryl; C₈ to C₂₀ aryl substituted with one to three groups selected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy, halogen, carboxy, cyano, C₁-C₆-alkanoyloxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfonyl, trifluoromethyl, hydroxy, C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoylamino, —OR′, SR′, —SO₂R′, —NHSO₂R′ or —NHCO₂R′; or a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, which may be substituted with up to three groups selected from C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy, C₂-C₆-alkoxycarbonyl and C₂-C₆-alkanoylamino; wherein R¹ can also be hydrogen, R⁶ branched or straight chain C₁ to C₂₀ alkyl, branched or straight chain C₁ to C₂₀ alkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR, C₃ to C₈ cycloalkyl, or C₃ to C₈ cycloalkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR, and wherein R is C₁ to C₆ alkyl and R′ is phenyl, naphthyl, or phenyl or naphthyl substituted with one to three groups selected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy or halogen; and n is
 2. 2. The compound of claim 1, wherein R¹ is hydrogen.
 3. The compound of claim 2, wherein R³ is methyl or ethyl.
 4. The compound of claim 3, wherein R⁶ is methyl or ethyl.
 5. A method of producing the compound of claim 1, comprising reacting a compound having the formula IV

wherein R¹ and R³ are, independently, branched or straight chain C₁ to C₂₀ alkyl; branched or straight chain C₁ to C₂₀ alkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₃ to C₈ cycloalkyl; C₃ to C₈ cycloalkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₆ to C₂₀ aryl; C₆ to C₂₀ aryl substituted with one to three groups selected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy, halogen, carboxy, cyano, C₁-C₆-alkanoyloxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfonyl, trifluoromethyl, hydroxy, C₂-C₈-alkoxycarbonyl, C₂-C₆-alkanoylamino, —OR′, SR′, —SO₂R′, —NHSO₂R′ and —NHCO₂R′; or a 5- or 6- membered aromatic ring containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, which may be substituted with up to three groups selected from C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy, C₂-C₆-alkoxycarbonyl and C₂-C₆-alkanoylamino; wherein R¹ can also be hydrogen, X is fluoride, chloride, bromide, or iodide, and n is 2, with a phosphite having the formula P(OR⁶)₃, wherein R⁶ is branched or straight chain C₁ to C₂₀ alkyl, branched or straight chain C₁ to C₂₀ alkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR, C₃ to C₈ cycloalkyl, or C₃ to C₈ cycloalkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR, and wherein R is C₁ to C₆ alkyl and R′ is phenyl, naphthyl, or phenyl or naphthyl substituted with one to three groups selected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy or halogen.
 6. The method of claim 5, wherein X is chloride or bromide.
 7. The method of claim 5, wherein R⁶ is methyl or ethyl.
 8. The method of claim 5, wherein the phosphite is present in the amount from 0.8 to 1.2 equivalents per 1.0 equivalent of the compound having the formula IV.
 9. A method of producing a compound having the formula IV,

wherein R¹ and R³ are, independently, branched or straight chain C₁ to C₂₀ alkyl; branched or straight chain C₁ to C₂₀ alkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₃ to C₈ cycloalkyl; C₃ to C₈ cycloalkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₈ to C₂₀ aryl; a C₆ to C₂₀ aryl substituted with one to three groups selected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy, halogen, carboxy, cyano, C₁-C₆-alkanoyloxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfonyl, trifluoromethyl, hydroxy, C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoylamino, —OR′, SR′, —SO₂R′, —NHSO₂R′ and —NHCO₂R′; or a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen which may be substituted with up to three groups selected from C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy, C₂-C₆-alkoxycarbonyl and C₂-C₆-alkanoylamino, wherein R¹ can also be hydrogen, X is fluoride, chloride, bromide, or iodide, and n is 2, comprising reacting a compound having the formula III

wherein R¹, R³, and R⁴ are, independently, branched or straight chain C₁ to C₂₀ alkyl; branched or straight chain C₁ to C₂₀ alkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₃ to C₈ cycloalkyl; C₃ to C₈ cycloalkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₆ to C₂₀ aryl; a C₆ to C₂₀ aryl substituted with one to three groups selected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy, halogen, carboxy, cyano, C₁-C₆-alkanoyloxy, C_(1-C) ₆-alkylthio, C₁-C₆-alkylsulfonyl, trifluoromethyl, hydroxy, C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoylamino, —OR′, SR′, —SO₂R′, —NHSO₂R′ and —NHCO₂R′; or a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, which may be substituted with up to three groups selected from C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy, C₂-C₆-alkoxycarbonyl and C₂-C₆-alkanoylamino, wherein R¹ can also be hydrogen, and n is 2, with a compound having the formula PX₃, wherein X is fluoro, chloro, bromo, or iodo, and wherein R is C₁ to C₆ alkyl and R′ is phenyl, naphthyl, or phenyl or naphthyl substituted with one to three groups selected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy or halogen.
 10. A method for producing a compound having formula VI

comprising reacting a compound having the formula V

with an aldehyde having the formula HC(O)R² in the presence of a base, wherein R¹, R², and R³ are, independently, branched or straight chain C₁ to C₂₀ alkyl; branched or straight chain C₁ to C₂₀ alkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₃ to C₈ cycloalkyl; C₃ to C₈ cycloalkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; C₆ to C₂₀ aryl; C₆ to C₂₀ aryl substituted with one to three groups selected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy, halogen, carboxy, cyano, C₁-C₆-alkanoyloxy, C₁-C₆-alkylthio, C₁-C₆-alkylsulfonyl, trifluoromethyl, hydroxy, C₂-C₆-alkoxycarbonyl, C₂-C₆-alkanoylamino, —OR′, SR′, —SO₂R′, —NHSO₂R′ and —NHCO₂R′; or a 5- or 6-membered aromatic ring containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, which may be substituted with up to three groups selected from C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, C₁-C₆-alkylthio, aryl, arylthio, aryloxy, C₂-C₆-alkoxycarbonyl and C₂-C₆-alkanoylamino; R⁶ is branched or straight chain C₁ to C₂₀ alkyl, branched or straight chain C₁ to C₂₀ alkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR, C₃ to C₈ cycloalkyl, or C₃ to C₈ cycloalkyl substituted with one to three groups selected from cyano, hydroxy, aryl, halogen, —OR, —CO₂R, and —OCOR; R is C₁ to C₆ alkyl and R′ is phenyl, naphthyl, or phenyl or naphthyl substituted with one to three groups selected from C₁-C₆-alkyl, C₆-C₁₀ aryl, C₁-C₆-alkoxy or halogen; R¹ and R² may, independently, be hydrogen; and n is
 2. 11. The method of claim 10, wherein the base comprises an amidine base or a guanidine base.
 12. The method of claim 10, wherein the base comprises 1,5-diazabicyclo(4.3.0)non-5-ene; 1,8-diazabicyclo(5.4.0)undec-7-ene, or tetramethylguanidine.
 13. The method of claim 10, wherein the base is present in the amount from 1.0 to 2.0 equivalents per 1.0 equivalent of the compound having the formula V.
 14. The method of claim 10, wherein the aldehyde is present in the amount from 0.8 to 1.5 equivalents per 1.0 equivalent of the compound having the formula V.
 15. The method of claim 10, wherein the aldehyde is acetaldehyde.
 16. The method of claim 10 wherein R¹ is hydrogen.
 17. The method of claim 16 wherein R² and R³ are methyl.
 18. The method of claim 16 wherein R² is methyl and R³ is ethyl.
 19. The method of claim 17 or 18 wherein R⁶ is methyl or ethyl. 